Pregnancy is a unique immunological situation because the fetus is not genetically identical to the mother. The placenta plays an important role in protecting the fetus from attack by the maternal immune system while at the same time protects the fetus from pathogens. The details of how the placental immune system accomplishes these seemingly contradictory tasks are largely unknown. Overview/Hypothesis: We hypothesize that the maternal immune cells of the placenta, specifically the macrophages located in the decidua (lining of the pregnant uterus), defend this organ against pathogens in a unique manner. Specific Aims: (1) To determine the decidual macrophage response to infection; (2) To investigate the role of IFN and interferon-inducible proteins with tetracopeptide repeats (IFITs) in placental host defense. Methods: We will study the placental innate immune responses to the facultative intracellular bacterial pathogen Listeria monocytogenes (LM). LM infection during pregnancy in humans and other mammals leads to pregnancy complications such as preterm labor. In addition to its clinical relevance, LM is highly amenable to experimental analysis. We will utilize a combination of primary human and mouse placental macrophages and placental tissue in vitro to investigate how these cells respond to LM, and evaluate how their response differs from that of other tissue-specific macrophages (Aim 1). To confirm our findings in vivo, we will employ a pregnant mouse model. In addition to wild type mice, we propose to use mice with specific genetic backgrounds in order to dissect the role of cytokine signaling pathways (e.g. IFN) in the defense against placental infection (Aim 2). Training Goal: The other major goal for this F32 training award is the rigorous post-doctoral research training of Dr. Gabrielle Rizzuto in microbial pathogenesis and placental biology with the concerted use of human and murine research tools. Expected Results: We predict the results of this project will be (1) a clearer understanding of how the maternal immune system interacts with pathogens in the placenta; and (2) that the trainee will be well-positioned to begin a successful independent career as a physician-scientist. Relevance: The leading cause of newborn death worldwide is pre-term birth, and infection of the placenta is the most common cause of pre-term birth. We will begin to tackle this problem with a unique approach using primary human placental tissues and an important human bacterial pathogen, in conjunction with the pregnant mouse, a genetically tractable model to confirm and expand the in vivo relevance of our findings.